Methotrexate (also known as MTX; N-(4-[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl) glutamic acid; 4-amino-N-10-methylpteroyl glutamic acid; 4-amino-10-methyl folic acid; methylaminopterin; and amethopterin) is a folic acid analog and antagonist. Methotrexate has been therapeutically employed in numerous chemotherapeutic applications, including the treatment of psoriasis, leukemia, cancers and other disorders resulting from cell proliferation. Methotrexate has also been used as an immunosuppressant and for treating dermatomyositis and rheumatoid arthritis.
Methotrexate has been shown to demonstrate therapeutic effects when administered orally or parenterally. For example, massive doses of methotrexate followed by leucovorin rescue are employed in the clinical treatment of certain neoplasms [Pratt et al., Cancer Chemother. Rep. Part 3, 6:13 (1975)]. However, when methotrexate is administered in amounts sufficient to produce the desired therapeutic effect, toxicity and other adverse effects have frequently been observed. In this regard, methotrexate has been reported to cause fetal death and/or congenital anomalies when administered to women of childbearing potential. Hepatotoxicity has also been observed as a result of the administration of methotrexate, with concomitant elevation in liver enzymes, fatty change, portal inflammation, fibrosis and cirrhosis. Methotrexate has also been associated with induced lung disease, bone marrow depression (with associated anemia, leukopenia and/or thrombocytopenia), diarrhea, ulcerative stomatitis and hemorrhagic enteritis.
Orally administered methotrexate has been found to be particularly effective for the treatment of psoriasis, a skin disease characterized by hyperproliferation. However, because of significant systemic toxicity, the use of methotrexate is limited primarily to the most serious and extensive cases of psoriasis and therefore is of limited utility when administered by that route. Because of the side effects associated with known means of administration of methotrexate, alternative means for administration have been examined. Topical application of methotrexate has been pursued, but has proven unsatisfactory for one reason or another. [see, e.g., Stewart et al., Arch. Dermatol. 106:357 (1972); Weinstein, Advances in Biology of the Skin, Vol. XII, Pharmacology and the Skin, ed. Montagna et al., pp. 287 (Appleton-Century-Crofts, New York 1969); Comaish et al., Arch. Dermatol. 100:99 (1969); Nurse, Arch. Dermatol. 87:258 (1963); Van Scott et al., J. Invest. Dermatol. 33:357 (1959)].
One such reason is that methotrexate is a water-soluble drug and as such does not readily penetrate the stratum corneum, the outermost layer of the skin. It also cannot easily penetrate the lower skin layers to reach the epidermal or other cells upon which it is to act. The hydrophobic stratum corneum layer of the skin acts like a sieve which, probably due to the water solubility of methotrexate, is impenetrable to more than very small amounts of compound. It is likely that this lack of penetration into the skin is one of the primary reasons for lack of efficacy of the drug when applied topically. This is supported by the finding that direct intralesional administration of methotrexate into psoriatic plaques, which avoids penetration of the skin, is associated with a decrease in mitotic activity and hence a decreased proliferation in the treated area.
Although previous studies have shown that, when topically applied, some methotrexate trickles through the stratum corneum, the amount passing through is far less than the amount originally applied to the skin. As a result, for topical application of methotrexate to be effective at all, methotrexate must be applied in highly excessive amounts which leads to toxic reactions and other side effects.
Many attempts have been made to increase the percutaneous penetration and absorption of methotrexate. Most methods involve attempts to alter the solubility characteristics of methotrexate or the vehicle by which it is topically applied. For example, McCullough et al. (J. Invest. Dermatol. 66:103 107 (1976)) applied methotrexate in combination with dimethylsulfoxide (80%) or dimethylacetamide (25%) as a vehicle, with no effect on penetration. Although a 0.1% retinoic acid vehicle did not increase penetration, a saturated solution of retinoic acid in aqueous ethanol produced a marked increase. Decyl methyl sulfoxide (2.5%) produced a 143-fold increase in penetration, which approaches levels sufficient to produce the desired therapeutic effect in lower skin layers. Lipid soluble methotrexate derivatives (such as the dimethyl ester of dichloromethotrexate) were also tested and exhibited small increases in penetration. Ball et al. (J. Invest. Dermatol. 79:710 (1982)) also observed an increase in penetration using "Vehicle N" (alcohol 47.5%, water, laureth 4, isopropyl alcohol 4%, propyleneglycol) from Neutrogena Corporation.
Weinstein et al. [Arch. Dermatol. 25:227 (1989)] reported that a topical formulation of methotrexate in 1-dodecylazacycloheptan-2-one produced improvement in psoriatic patients. However, there were no statistical differences in drug treated versus vehicle treated sites one week after therapy was discontinued. Enhancement of methotrexate penetration into the affected skin in patients with psoriasis resulted in emprovement in the psoriatic plaques with no evidence of systemic side effects.
However, these methods have generally been shown to be disadvantageous in that the solvents used to enhance penetration may not be suitable for human use and to do so may present undesirable effects, including skin dehydration, irritation of sensitive skin, photosensitivity and changes in the lipid protein structure of the membranes.
Thus, the development of a pharmaceutical composition containing methotrexate which could be used locally on psoriatic plaques and would have a minimal systemic absorption would be expected to drastically reduce the toxicity of methotrexate and increase its utility for treatment of psoriasis and other disorders. The ability to safely and efficaciously deliver methotrexate into the skin for the treatment of psoriasis and other hyperproliferative disorders is a requisite to widespread therapeutic use. To date, conventionally used formulations do not satisfactorily meet these requirements, thus impeding the clinical utility of methotrexate.